1. Field of Invention
The 6-thioalkyl pyrimidine-2-thioalkyl and alkylether derivatives of Formula I are useful in the treatment of individuals who are HIV positive, whether or not they show AIDS symptoms at the present time. The 6-thioalkyl pyrimidine-2-thioalkyl and alkylether derivatives of Formula I are useful in the preparation of the pyrimidine-thioalkyl and alkylether derivatives of Formula I.
2. Description of the Related Art
U.S. Pat. No. 5,025,016 (and EP 124 630) pyrimidine-thioalkyl pyridine derivatives corresponding to the general formula ##STR2## in which R.sub.1 to R.sub.4, independently of one another, represent hydrogen, lower alkyl, halogen, amino or hydroxy groups, R.sub.5 represents a free electron pair or a lower alkyl group, a halogen atom, m has the value 0 or 1, the pyrimidine-thioalkyl group being bonded in the 2-, 3- or 4-position of the pyridine ring, and to therapeutically compatible acid addition salts thereof. The compounds allegedly exhibit surprisingly improved bronchosecretolytic and myucolytic activity as well as having been found to show antiphlogistic activity.
J. Med Chem. 1987, 30, 547-551 describes various 2-[(pyridinylmethyl)thiol-pyrimidine derivatives and the influence thereof on bronchosecretolytic properties in the phenol red screening model of the mouse in comparison to the known drug ambroxol.
EP 477 778 (Derwent 92-106190/14) describes various benzene, pyridine and pyrimidine derivatives as ACAT enzyme inhibitors, for treating arteriosclerosis, and cerebrovascular disease.
J. Org. Chem, 1954, 19, 1793-1801 describes pyrimidine derivatives, including 2-benzylmercapto-4-amino-6-pyrimidinol, 2-benzylmercapto-4-amino-6-chloropyrimidine, 2-benzylmercapto-4-amino-6-diethylaminopyrimidine as well as analogs of 6-dimethylaminopurine.
British Patent 744,867 (CA 51:2063i) describes various 2-R'-S-6-RR'N-substituted 4-aminopyrimidines.
An estimated one to one and one-half million people in the United States are infected with a human retrovirus, the human immunodeficiency virus type I (HIV-1) which is the etiological agent of acquired immunodeficiency syndrome, AIDS, see Science, 661-662 (1986). Of those infected, an estimated two hundred and fifty thousand people will develop AIDS in the next five years, see Science, 1352-1357 (1985). On Mar. 20, 1987, the FDA approved the use of the compound, AZT (zidovudine), to treat AIDS patients with a recent initial episode of pneumocystis carinii pneumonia, AIDS patients with conditions other than pneumocystis carinii pneumonia or patients infected with the virus with an absolute CD4 lymphocyte count of less than 200/mm.sup.3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication.
U.S. Pat. No. 4,724,232 claims a method of treating humans having acquired immunodeficiency syndrome utilizing 3'-azido-3'-deoxy-thymidine (azidothymidine, AZT).
It is known in the art that certain antibiotics and polyanionic dyes inhibit retrovirus reverse transcriptase.
Many publications have reported the ability of various sulfated compounds to inhibit virus replication, including HIV.
Nature 343, 470 (1990) and Science 250, 1411 (1990) disclose potent benzodiazepin type reverse transcriptase inhibitors. The compounds of the present invention are not benzodiazepin type compounds.
J. Org. Chem. 1962, 27, 181-185 describes various 2-benzylthio pyrimidine derivatives, including 4-chloro-5-methyl-2-[(phenylmethyl)thio]-pyrimidine, 4-chloro-5-methyl-2-[ [(2,4-dichloro-phenyl)methyl]thio]-pyrimidine, 4-chloro-5-methyl-2-[[(2-chloro-phenyl)methyl]thio]-pyrimidine, and 4-chloro-5-methyl-2-[[(4-chloro-phenyl)methyl]thio]-pyrimidine and their activity as antitumor compounds in screens against SA-180, CA 755, and L-1210 tumor systems.
J. Med. Chem. 1977, 20, 88-92 describes 2-alkoxy and 2-alkylthio-4-amino pyrimidines, including 2-[(phenylmethyl)thio]4-pyrimidinamine, 2-[[(4-chlorophenyl)methyl]thio]-4-pyrimidinamine, 2-[(3-pyridinylmethyl)thio]4-pyrimidinamine, and 2-(phenylmethoxy)-4-pyrimidinamine, and their activity as inhibitors of deoxycytidine kinase.
Collect. Czech. Chem. Comm. 1975, 40, 1078-1088 (CA 83:114326e) describes 5-(3-iodopropargyloxy)pyrimidines as effective fungistatics.
Synthesis 1981, 397-400 describes peroxypyrimidines.
J. Org. Chem. 1961, 26, 1884 describes the synthesis of aziridinyl pyrimidines as analogs of methioprim.
J. Med. Chem. 1991, 34, 315-319 describes derivatives of thiouracil which have dihydroxyboryl group at the C-5 position. These compounds are useful for B neutron-capture therapy of malignant melanoma.
WO 96/35678 (published Nov. 14, 1996) discloses various alpha-substituted pyrimidine-2-thioalkyl and alkylether compounds of Formula A ##STR3## wherein R.sub.4 is selected from the group consisting of --H, --OH, halo or --NR.sub.15 R.sub.16 where R is --H and R.sub.16 is --H, C.sub.1 -C.sub.6 alkyl, --NH.sub.2 or R.sub.15 and R.sub.16 taken together with the --N form 1-pyrrolidino, 4-morpholino or 1-piperidino;
R.sub.5 is selected from the group consisting of --H, --C.sub.2 H.sub.4 OH, --C.sub.2 H.sub.4 --O-TBDMS, halo, --C.sub.3 -C.sub.6 cycloalkyl, C.sub.1 -C.sub.3 alkoxy, --CH.sub.2 CH.sub.2 Cl or C.sub.1 -C.sub.4 alkyl, with the proviso that R.sub.5 is not isobutyl; PA1 or R.sub.4 and R.sub.5 are taken together to form a five or six-membered saturated or unsaturated ring which together with the pyrimidine ring form the group consisting of 7H-pyrrolo[2,3-d]pyrimidine, 5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine, furo[2,3-pyrimidine, 5,6-dihydro-furo[2,3-d]pyrimidine, thieno[2,3-d]pyrimidine, 5,6-dihydro-thieno[2,3-d]pyrimidine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-purine, pyrimido[4,5-d]pyrimidine, pteridine, pyrido[2,3-dipyrimidine, or quinazoline, where the unsaturated ring may be optionally substituted with 1, 2 or 3, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --OH, --CH.sub.2 OH, or --(CH.sub.2).sub.n --N(R.sub.31)(R.sub.32), --C.sub.3 -C.sub.8 cycloalkyl, --CF.sub.3, -halo, --CO.sub.2 (R.sub.31), --CON(R.sub.31)(R.sub.32), --CO(R.sub.31), --(CH.sub.2).sub.n N(R.sub.31)(CO(R.sub.33)), --(CH.sub.2).sub.n N(R.sub.31) (SO.sub.2 (R.sub.33)), and the saturated ring may be optionally substituted with 1, 2 or 3, --C.sub.1 -C.sub.6 alkyl, --C.sub.1 -C.sub.6 alkoxy, --OH, --CH.sub.2 OH, or --(CH.sub.2).sub.n --N(R.sub.31)(R.sub.32) or one oxo (.dbd.O); and PA1 R.sub.6 is selected from the group consisting of --H, --OH, halo (preferably --Cl), --CN, --CF.sub.3, --CO.sub.2 (R.sub.61), --C(O)R.sub.61 or --C(O)N(R.sub.61)(R.sub.62) where R.sub.61 and R.sub.62 are the same or different and are selected from PA1 where n is 0-3 and R.sub.31, R.sub.32, and R.sub.33 are the same or different and are selected from PA1 or a member selected from the group consisting of: PA1 R.sub.41 and R.sub.42, being the same or different, are selected from the group consisting of --H and C.sub.1 -C.sub.4 alkyl; PA1 R.sub.12 is selected from the group consisting of --H, C.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.6 cycloalkyl, --CN, --C(O)NH.sub.2, --C(O)N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), --CO.sub.2 H, --CO.sub.2 (C.sub.1 -C.sub.6 alkyl), --CH.sub.2 OH, --CH.sub.2 NH.sub.2 or --CF.sub.3 ; PA1 R.sub.13 is selected from the group consisting of --H, C.sub.1 -C.sub.6 alkyl or --CF.sub.3 ; PA1 Y is selected from --S--, --S(O)--, --S(O).sub.2, or --O--; PA1 R.sub.4 is selected from the group consisting of --H, --OH, halo or --NR.sub.15 R.sub.16 where R.sub.15 is --H and R.sub.16 is --H, C.sub.1 -C.sub.6 alkyl, --NH.sub.2 or R.sub.15 and R.sub.16 taken together with the --N form 1-pyrrolidino, 4-morpholino or 1-piperidino; PA1 R.sub.5 is selected from the group consisting of --H, --C.sub.2 H.sub.4 OH, --C.sub.2 H.sub.4 --O-TBDMS, halo, --C.sub.3 -C.sub.6 cycloalkyl, C.sub.1 -C.sub.3 alkoxy, --CH.sub.2 CH.sub.2 Cl or C.sub.1 -C.sub.4 alkyl, with the proviso that R.sub.5 is not isobutyl; PA1 or R.sub.4 and R.sub.5 are taken together to form a five or six-membered saturated or unsaturated ring which together with the pyrimidine ring form the group consisting of 7H-pyrrolo[2,3-d]pyrimidine, 5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine, furo[2,3-d]pyrimidine, 5,6-dihydro-furo[2,3-d]pyrimidine, thieno[2,3-d]pyrimidine, 5,6-dihydro-thieno[2,3-d]pyrimidine, 1H-pyrazolo [3,4-d]pyrimidine, 1H-purine, pyrimido[4,5-d]pyrimidine, pteridine, pyrido[2,3-d]pyrimidine, or quinazoline, where the unsaturated ring may be optionally substituted with 1, 2 or 3, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --OH, --CH.sub.2 OH, or --(CH.sub.2).sub.n --N(R.sub.31)(R.sub.32), --C.sub.3 -C.sub.8 cycloalkyl, --CF.sub.3, -halo, --CO.sub.2 (R.sub.31), --CON(R.sub.31)(R.sub.32), --CO(R.sub.31), --(CH.sub.2).sub.n N(R.sub.31)(CO(R.sub.33)), (CH.sub.2).sub.n N(R.sub.31) (SO.sub.2 (R.sub.33)), and the saturated ring may be optionally substituted with 1, 2 or 3, --C.sub.1 -C.sub.6 alkyl, --C.sub.1 -C.sub.6 alkoxy, --OH, --CH.sub.2 OH, or --(CH.sub.2).sub.n --N(R.sub.31)(R.sub.32) or one oxo (.dbd.O); and PA1 R.sub.6 is --S--C.sub.1-6 alkyl (preferably --S--CH.sub.3); PA1 R.sub.4 is selected from the group consisting of --H or --NR.sub.15 R.sub.16 where R.sub.15 is --H and R.sub.16 is --H, C.sub.1 -C.sub.6 alkyl, --NH.sub.2 or R.sub.15 and R.sub.16 taken together with the --N form 1-pyrrolidino, 4-morpholino or 1-piperidino; and PA1 R.sub.6 is --S--C.sub.1 -C.sub.6 alkyl (preferably --S--CH.sub.3). PA1 3-isoquinolinyl, 1-isoquinolinyl, 2-quinolinyl, 3-quinolinyl, 3-(5,6,7,8-tetrahydro)-isoquinolinyl, 1-(5,6,7,8-tetrahydro)-isoquinolinyl, 2-(5,6,7,8-tetrahydro)-quinolinyl, 3-(5,6,7,8-tetrahydro)-quinolinyl, 3-(5,6-dihydro)-2H-2-pyrindinyl, 1-(5,6-dihydro)-2H-2-pyrindinyl, 2-(5,6-dihydro)-1H-1-pyrindinyl, 3-(5,6-dihydro)-1H-1-pyrindinyl, 5-furo[2,3-c]pyridinyl, 6-furo[3,2-c]pyridinyl, 4-furo[3,2-c]pyridinyl, 7-furo[2,3-c]pyridinyl, 6-furo[2,3-b]pyridinyl, 5-furo[3,2-b]pyridinyl, 5-(2,3-dihydro)-furo[2,3-c]pyridinyl, 6-(2,3-dihydro)-furo[3,2-c]pyridinyl, 4-(2,3-dihydro)-furo[3,2-c]pyridinyl , 7-(2,3-dihydro)-furo[2,3-c]pyridinyl, 6-(2,3-dihydro)-furo[2,3-b]pyridinyl, 5-(2,3-dihydro)-furo[3,2-b]pyridinyl, 6-(1,3-dihydro)-furo[3,4-c]pyridinyl , 4-(1,3-dihydro)-furo[3,4-c]pyridinyl, 2-(5,7-dihydro)-furo[3,4-b]pyridinyl, 6-(3,4-dihydro)-2H-pyrano[2,3-c]pyridinyl, 6-(3,4-dihydro)-1H-pyrano[3,4-c]pyridinyl, 7-(3,4-dihydro)-1H-pyrano[4,3-c]pyridinyl, 7-(3,4-dihydro)-2H-pyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-2H-pyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-1H-pyrano[4,3-c]pyridinyl, 8-(3,4-dihydro)-1H-pyrano[3,4-c]pyridinyl, 8-(3,4-dihydro)-2H-pyrano[2,3-c]pyridinyl, 7-(3,4-dihydro)-2H-pyrano[2,3-b]pyridinyl, 2-(5,6-dihydro)-1H-pyrano[3,4-b]pyridinyl, 2-(5,6-dihydro)-2H-pyrano[4,3-b]pyridinyl, or 6-(3,4-dihydro)-2H-pyrano[3,2-b]pyridinyl; wherein such member is optionally substituted as described above. PA1 phenyl optionally substituted with one, 2 or 3 C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, or nitro; 2- or 3-pyridinyl optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, --C.sub.3 -C.sub.8 cycloalkyl, --CF.sub.3, --NO.sub.2, -halo, --OH, --CN, phenyl, phenylthio, -styryl, --CO.sub.2 (R.sub.31), --CON(R.sub.31)(R.sub.32), --CO(R.sub.31), --(CH.sub.2).sub.n --N(R.sub.31)(R.sub.32), --C(OH)(R.sub.31)(R.sub.33), (CH.sub.2).sub.n N(R.sub.31)(CO(R.sub.33)), (CH.sub.2).sub.n N(R.sub.31)(SO.sub.2 (R.sub.33)); naphthyl optionally substituted with one or 2 C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.1 -C.sub.3 alkylthio or nitro; --C.tbd.CH; as well as 3-isoquinolinyl, 1-isoquinolinyl, 2-quinolinyl, 3-quinolinyl, 3-(5,6,7,8-tetrahydro)-isoquinolinyl, 1-(5,6,7,8-tetrahydro)-isoquinolinyl, 2-(5,6,7,8-tetrahydro)-quinolinyl, 3-(5,6,7,8-tetrahydro)-quinolinyl, 3-(5,6-dihydro)-2H-2-pyrindinyl, 1-(5,6-dihydro)-2H-2-pyrindinyl, 2-(5,6-dihydro)-1H-1-pyrindinyl, 3-(5,6-dihydro)-1H-1-pyrindinyl, 5-furo[2,3-c]pyridinyl, 6-furo[3,2-c]pyridinyl, 4-furo[3,2-c]pyridinyl, 7-furo[2,3-c]pyridinyl, 6-furo[2,3-b]pyridinyl, 5-furo[3,2-b]pyridinyl, 5-(2,3-dihydro)-furo[2,3-c]pyridinyl, 6-(2,3-dihydro)-furo[3,2-c]pyridinyl, 4-(2,3-dihydro)-furo[3,2-c]pyridinyl , 7-(2,3-dihydro)-furo[2,3-c]pyridinyl, 6-(2,3-dihydro)-furo[2,3-b]pyridinyl, 5-(2,3-dihydro)-furo[3,2-b]pyridinyl, 6-(1,3-dihydro)-furo[3,4-c]pyridinyl , 4-(1,3-dihydro)-furo[3,4-c]pyridinyl, 2-(5,7-dihydro)-furo[3,4-b]pyridinyl, 6-(3,4-dihydro)-2H-pyrano[2,3-c]pyridinyl, 6-(3,4-dihydro)-1H-pyrano[3,4-c]pyridinyl, 7-(3,4-dihydro)-2H-pyrano[4,3-c]pyridinyl, 7-(3,4-dihydro)-2H-pyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-1H-pyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-2H-pyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-2H-pyrano[3,4-c]pyridinyl, 5-(3,4-dihydro)-2H-pyrano[4,3-c]pyridinyl, 8-(3,4-dihydro)-1H-pyrano[3,4-c]pyridinyl, 8-(3,4-dihydro)-2H-pyrano[2,3-c]pyridinyl, 7-(3,4-dihydro)-2H-pyrano[2,3-b]pyridinyl, 2-(5,6-dihydro)-1H-pyrano[3,4-b]pyridinyl, 2-(5,6-dihydro)-2H-pyrano[4,3-b]pyridinyl, 6-(3,4-dihydro)-2H-pyrano[3,2-b]pyridinyl, 5-1H-pyrrolo[2,3-c]pyridinyl, 6-1H-pyrrolo[3,2-c]pyridinyl, 4-1H-pyrrolo[3,2-c]pyridinyl, 7-1H-pyrrolo[2,3-c]pyridinyl, 6-1H-pyrrolo[2,3-b]pyridinyl, 5-1H-pyrrolo[3,2-b]pyridinyl, 5-(2,3-dihydro)-1H-pyrrolo[2,3-c]pyridinyl, 6-(2,3-dihydro)-1H-pyrrolo[3,2-c]pyridinyl, 4-(2,3-dihydro)-1H-pyrrolo[3,2-c]pyridinyl, 7-(2,3-dihydro)-1H-pyrrolo[2,3-c]pyridinyl, 6-(2,3-dihydro)-1H-pyrrolo[2,3-b]pyridinyl, 5-(2,3-dihydro)-1H-pyrrolo[3,2-b]pyridinyl, 6-(1,3-dihydro)-1H-pyrrolo[3,4-c]pyridinyl, 4-(1,3-dihydro)-1H-pyrrolo[3,4-c]pyridinyl, 2-(5,7-dihydro)-1H-pyrrolo[3,4-b]pyridinyl, 6-1,7-naphthyridinyl, 6-2,7-naphthyridinyl, 7-2,6-naphthyridinyl, 7-1,6-naphthyridinyl, 5-1,6-naphthyridinyl, 5-2,6-naphthyridinyl, 8-2,7-naphthyridinyl, 8-1,7-naphthyridinyl, 7-1,8-naphthyridinyl, 2-1,7-naphthyridinyl, 2-1,6-naphthyridinyl, 6-1,5-naphthyridinyl, 6-(1,2,3,4-tetrahydro)-1,7-naphthyridinyl, 6-(1,2,3,4-tetrahydro)-2,7-naphthyridinyl, 7-(1,2,3,4-tetrahydro)-2,6-naphthyridinyl, 7-(1,2,3,4-tetrahydro)-1,6-naphthyridinyl, 5-(1,2,3,4-tetrahydro)-1,6-naphthyridinyl, 5-(1,2,3,4-tetrahydro)-2,6-naphthyridinyl, 8-(1,2,3,4-tetrahydro)-2,7-naphthyridinyl, 8-(1,2,3,4-tetrahydro)-1,7-naphthyridinyl, 7-(1,2,3,4-tetrahydro)-1,8-naphthyridinyl, 2-(5,6,7,8-tetrahydro)-1,7-naphthyridinyl, 2-(5,6,7,8-tetrahydro)-1,6-naphthyridinyl, 6-(1,2,3,4-tetrahydro)-1,5-naphthyridinyl, 1-naphthyl, 2-naphthyl, 5-(1,2,3,4-tetrahydro)-naphthyl, 6-(1,2,3,4-tetrahydro)-naphthyl, 4-(2,3-dihydro)-1H-indenyl, 5-(2,3-dihydro)-1H-indenyl, 5-benzofuranyl, 4-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 5-(2,3-dihydro)-benzofuranyl, 4-(2,3-dihydro)-benzofuranyl, 6-(2,3-dihydro)-benzofuranyl, 7-(2,3-dihydro)-benzofuranyl, 4-(1,3-dihydro)-isobenzofuran, 5-(1,3-dihydro)-isobenzofuran, 4-1H-indolyl, 5-1H-indolyl, 6-1H-indolyl, 7-1H-indolyl, 4-(2,3-dihydro)-1H-indolyl, 5-(2,3-dihydro)-1H-indolyl, 6-(2,3-dihydro)-1H-indolyl, 7-(2,3-dihydro)-1H-indolyl, 4-(1,3-dihydro)-1H-isoindolyl, 5-(1,3-dihydro)-1H-isoindolyl, 5-(3,4-dihydro)-1H-2-benzopyranyl, 6-(3,4-dihydro)-1H-2-benzopyranyl, 7-(3,4-dihydro)-1H-2-benzopyranyl, 8-(3,4-dihydro)-1H-2-benzopyranyl, 5-(3,4-dihydro)-2H-1-benzopyranyl, 6-(3,4-dihydro)-2H-1-benzopyranyl, 7-(3,4-dihydro)-2H-1-benzopyranyl, 8-(3,4-dihydro)-2H-1-benzopyranyl, 5-(1,2,3,4-tetrahydro)-isoquinolinyl, 6-(1,2,3,4-tetrahydro)-isoquinolinyl, 7-(1,2,3,4-tetrahydro)-isoquinolinyl , 8-(1,2,3,4-tetrahydro)-isoquinolinyl, 5-(1,2,3,4-tetrahydro)-quinolinyl, 6-(1,2,3,4-tetrahydro)-quinolinyl, 7-(1,2,3,4-tetrahydro)-quinolinyl, 8-(1,2,3,4-tetrahydro)-quinolinyl, 5-thieno[2,3-c]pyridinyl, 6-thieno[3,2-c]pyridinyl, 4-thieno[3,2-c]pyridinyl, 7-thieno[2,3-c]pyridinyl, 6-thieno[2,3-b]pyridinyl, 5-thieno[3,2-b]pyridinyl, 5-(2,3-dihydro)-thieno[2,3-c]pyridinyl, 6-(2,3-dihydro)-thieno[3,2-c]pyridinyl, 4-(2,3-dihydro)-thieno[3,2-c]pyridinyl, 7-(2,3-dihydro)-thieno[2,3-c]pyridinyl, 6-(2,3-dihydro)-thieno[2,3-b]pyridinyl, 5-(2,3-dihydro)-thieno[3,2-b]pyridinyl, 6-(1,3-dihydro)-thieno[3,4-c]pyridinyl, 4-(1,3-dihydro)-thieno[3,4-c]pyridinyl, 2-(5,7-dihydro)-thieno[3,4-b]pyridinyl, 6-(3,4-dihydro)-2H-thiopyrano[2,3-c]pyridinyl, 6-(3,4-dihydro)-1H-thiopyrano[3,4-c]pyridinyl, 7-(3,4-dihydro)-1H-thiopyrano[4,3-c]pyridinyl, 7-(3,4-dihydro)-2H-thiopyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-2H-thiopyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-1H-thiopyrano[4,3-c]pyridinyl, 8-(3,4-dihydro)-1H-thiopyrano[3,4-c]pyridinyl, 8-(3,4-dihydro)-2H-thiopyrano[2,3-c]pyridinyl, 7-(3,4-dihydro)-2H-thiopyrano[2,3-b]pyridinyl, 2-(5,6-dihydro)-1H-thiopyrano[3,4-b]pyridinyl, 2-(5,6-dihydro)-2H-thiopyrano[4,3-b]pyridinyl, 6-(3,4-dihydro)-2H-thiopyrano[3,2-b]pyridinyl, 5-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl, 5-(2,3-dihydro)-benzo[b]thiophenyl, 4-(2,3-dihydro)-benzo[b]thiophenyl, 6-(2,3-dihydro)-benzo[b]thiophenyl, 7-(2,3-dihydro)-benzo[b]thiophenyl, 4-(1,3-dihydro)-benzo[c]thiophenyl, 5-(1,3-dihydro)-benzo[c]thiophenyl, 5-(3,4-dihydro)-1H-2-benzothiopyranyl, 6-(3,4-dihydro)-1H-2-benzothiopyranyl, 7-(3,4-dihydro)-1H-2-benzothiopyranyl, 8-(3,4-dihydro)-1H-2-benzothiopyranyl, 5-(3,4-dihydro)-2H-1-benzothiopyranyl, 6-(3,4-dihydro)-2H-1-benzothiopyranyl, 7-(3,4-dihydro)-2H-1-benzothiopyranyl, 8-(3,4-dihydro)-2H-1-benzothiopyranyl, PA1 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 1-cyclohexenyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-imidazolyl, 4-imidazolyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-oxazolyl, 4-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl, 5-phenyl-3-isoxazolyl, 4-thiazolyl, 3-methyl-2-pyrazinyl, 5-methyl-2-pyrazinyl, 6-methyl-2-pyrazinyl, 5-chloro-2-thienyl, 3-furyl, benzofuran-2-yl, benzothien-2-yl, 2H-1-benzopyran-3-yl, 2,3-dihydrobenzopyran-5-yl, 2,3-dihydrobenzofuran-2-yl, 1-methylimidazol-2-yl, quinoxalin-2-yl, isoquinolin-3-yl, piperon-5-yl, 4,7-dichlorobenzoxazol-2-yl, 4,6-dimethylpyrimidin-2-yl, 4-methylpyrimidin-2-yl, 2,4-dimethylpyrimidin-6-yl, 2-methylpyrimidin-4-yl, 4-methylpyrimidin-6-yl, 6-chloropiperon-5-yl, 5-chloroimidazo[1,2-a]pyridin-2-yl, 1-H-inden-3-yl, 1-H-2-methyl-inden-2-yl, 3,4-dihydronaphth-1-yl, S-4-isopropenyl-cyclohexen-1-yl and 4-dihydronaphth-2-yl. PA1 3-isoquinolinyl, 1-isoquinolinyl, 2-quinolinyl, 3-quinolinyl, 3-(5,6,7,8-tetrahydro)-isoquinolinyl, 1-(5,6,7,8-tetrahydro)-isoquinolinyl, 2-(5,6,7,8-tetrahydro)-quinolinyl, 3-(5,6,7,8-tetrahydro)-quinolinyl, 3-(5,6-dihydro)-2H-2-pyrindinyl, 1-(5,6-dihydro)-2H-2-pyrindinyl, 2-(5,6-dihydro)-1H-1-pyrindinyl, 3-(5,6-dihydro)-1H-1-pyrindinyl, 5-furo[2,3-c]pyridinyl, 6-furo[3,2-c]pyridinyl, 4-furo[3,2-c]pyridinyl, 7-furo[2,3-c]pyridinyl, 6-furo[2,3-b]pyridinyl, 5-furo[3,2-b]pyridinyl, 5-(2,3-dihydro)-furo[2,3-c]pyridinyl, 6-(2,3-dihydro)-furo[3,2-c]pyridinyl, 4-(2,3-dihydro)-furo[3,2-c]pyridinyl , 7-(2,3-dihydro)-furo[2,3-c]pyridinyl, 6-(2,3-dihydro)-furo[2,3-b]pyridinyl, 5-(2,3-dihydro)-furo[3,2-b]pyridinyl, 6-(1,3-dihydro)-furo[3,4-c]pyridinyl , 4-(1,3-dihydro)-furo[3,4-c]pyridinyl, 2-(5,7-dihydro)-furo[3,4-b]pyridinyl, 6-(3,4-dihydro)-2H-pyrano[2,3-c]pyridinyl, 6-(3,4-dihydro)-1H-pyrano[3,4-c]pyridinyl, 7-(3,4-dihydro)-1H-pyrano[4,3-c]pyridinyl, 7-(3,4-dihydro)-2H-pyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-2H-pyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-1H-pyrano[4,3-c]pyridinyl, 8-(3,4-dihydro)-1H-pyrano[3,4-c]pyridinyl, 8-(3,4-dihydro)-2H-pyrano[2,3-c]pyridinyl, 7-(3,4-dihydro)-2H-pyrano[2,3-b]pyridinyl, 2-(5,6-dihydro)-1H-pyrano[3,4-b]pyridinyl, 2-(5,6-dihydro)-2H-pyrano[4,3-b]pyridinyl, 6-(3,4-dihydro)-2H-pyrano[3,2-b]pyridinyl.
--H, PA2 C.sub.1 -C.sub.6 alkyl, PA2 phenyl optionally substituted with 1, 2, or 3-halo, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --CF.sub.3, --OH, --CN, PA2 or where R.sub.61 and R.sub.62 taken together with the attached nitrogen to form a ring selected from -pyrrolidinyl, -piperidinyl, -4-morpholinyl, -4-thiomorpholinyl, -4-piperazinyl, or -4-(C.sub.1 -C.sub.6 alkyl)piperazinyl; PA2 --H, PA2 C.sub.1 -C.sub.6 alkyl, PA2 phenyl optionally substituted with 1, 2, or 3-halo, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --CF.sub.3, --OH or --CN, PA2 1-cyclohexenyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-imidazolyl, 4-imidazolyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-oxazolyl, 4-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl, 5-phenyl-3-isoxazolyl, 4-thiazolyl, 3-methyl-2-pyrazinyl, 5-methyl-2-pyrazinyl, 6-methyl-2-pyrazinyl, 5-chloro-2-thienyl, 3-furyl, benzofuran-2-yl, benzothien-2-yl, 2H-1-benzopyran-3-yl, 2,3-dihydrobenzopyran-5-yl, 1-methylimidazol-2-yl, quinoxalin-2-yl, piperon-5-yl, 4,7-dichlorobenzoxazol-2-yl, 4,6-dimethyl-pyrimidin-2-yl, 4-methylpyrimidin-2-yl, 2,4-dimethylpyrimidin-6-yl, 2-methylpyrimidin-4-yl, 4-methylpyrimidin-6-yl, 6-chloropiperon-5-yl, 5-chloroimidazo[1,2-a]pyridin-2-yl, 1-H-inden-3-yl, 1-H-2-methyl-inden-2-yl, 3,4-dihydronaphth-1-yl, S-4-isopropenylcyclohexen-1-yl or 4-dihydronaphth-2-yl; where R.sub.53 is selected from the group consisting of --H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, phenyl (optionally substituted with 1, 2, or 3-halo, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --CF.sub.3, --OH, --CN), or a five or six-membered unsaturated ring containing 0 or 1 oxygen, nitrogen or sulfur, where the unsaturated ring may be optionally substituted with --H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --OH, --CH.sub.2 OH, or --(CH.sub.2).sub.n --N(R.sub.31)(R.sub.32); where R.sub.54 and R.sub.55 being the same or different are selected from --H. C.sub.1 -C.sub.6 alkyl, allyl, or phenyl (optionally substituted with 1, 2, or 3-halo, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or --CF.sub.3), or taken together with the attached nitrogen to form a ring selected from -pyrrolidinyl, -piperidinyl, -4-morpholinyl, -4-thiomorpholinyl, -4-piperazinyl, -4-(1-C.sub.1 -C.sub.6 alkyl)piperazinyl;
with the overall proviso that R.sub.4 and R.sub.6 are not both --H; and with the further proviso that and R.sub.12 and R.sub.13 are not both --H except when R.sub.6 is selected from --CN, --F.sub.3, --CO.sub.2 (R.sub.61), --C(O)R.sub.61 or --C(O)N(R.sub.61)(R.sub.62), or R.sub.1 is selected from --CO.sub.2 R.sub.53 or --C(O)N(R.sub.54)(R.sub.55).